The fundamental hypothesis guiding this proposal is that adenosine release during acute intermittent hypoxia (AIM) modulates the capacity for plasticity in respiratory motor control. Specifically, we postulate that adenosine 2A receptor activation profoundly modulates a well-established model of AlH-induced respiratory plasticity known as phrenic long-term facilitation (pLTF). Preliminary data have demonstrated that adenosine A2A receptor antagonists greatly enhance pLTF following AIM and that the relevant A2A receptors are located in cervical spinal regions associated with the phrenic motor nucleus. AlH-induced pLTF requires serotonin receptor activation and new protein synthesis, including new synthesis of brain derived neurotrophic factor (BDNF). BDNF activates its high affinity receptor tyrosine kinase, TrkB, subsequently leading to pLTF. Reactive oxygen species (specifically superoxide anions derived from NADPH oxidase) are necessary for pLTF, most likely by inhibition of serine/threonine protein phosphatases, an important inhibitory constraint to pLTF. The major goal during this project period is to test the specific hypothesis that A2A receptors modulate these same cellular/synaptic elements known to play critical roles in the mechanism of pLTF. A detailed understanding of mechanisms whereby A2A receptors modulate respiratory plasticity may guide the development of novel therapeutic approaches to treat patients with severe ventilatory control disorders, such as obstructive sleep apnea and respiratory insufficiency in patients with spinal cord injury or neurodegenerative disease (e.g., ALS). Three specific aims will be pursued using a multidisciplinary approach: Aim 1: To test the hypothesis that spinal A2A receptor antagonists enhance pLTF by modulating cellular mechanisms normally giving rise to pLTF. Aim 2: To test the hypothesis that spinal A2A receptor antagonists enhance pLTF by a mechanism that requires reactive oxygen species formation. Aim 3: To test the hypothesis that spinal A2A receptor antagonists modulate serine-threonine protein phosphatase activity, thereby enhancing pLTF [unreadable] [unreadable] [unreadable]